Substituted pyrazoles as estrogen receptor ligands

Abstract

The invention provides a compound of formula (I) wherein G is a pyrazole ring as defined in the specification and R 4 , R 5 , R 6 and R 7 are as defined in the specification; or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.

The invention claimed is: 
     
       1. A compound of formula (I) or a pharmaceutically acceptable ester, amide, solvate or salt thereof, or a salt of such an ester or amide, or a solvate of such an ester, amide or salt, 
       
         
           
           
               
               
           
         
       
       wherein G represents one of the groups: 
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting of halogen, cyano, nitro, OR A , N(R B ) 2 , —C(O)C 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, haloC 2-6 alkenyl, dihaloC 2-6 alkenyl, trihaloC 2-6 alkenyl, cyanoC 1-6 alkyl, C 1-4 alkoxyC 1-6  alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, phenyl, benzyl, and 5-10 membered heterocyclyl, wherein said benzyl or heterocyclyl is either unsubstituted or said phenyl, benzyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR A , N(R B ) 2 , halogen, cyano, nitro, —C(O)C 1-4 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, dihaloC 1-6 alkyl and trihaloC 1-6 alkyl; 
         R 2  is selected from the group consisting of —CH═N—OH, and —C(NH 2 )═N—OH; 
         R 3  is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl; haloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, phenyl, benzyl and 5-10 membered heterocyclyl wherein said benzyl or heterocyclyl is either unsubstituted or said phenyl, benzyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR A , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, dihaloC 1-6 alkyl and trihaloC 1-6 alkyl; 
         and wherein only one of R 1  and R 3  may be a substituted or unsubstituted phenyl; 
         each of R 4 , R 5 , R 6  and R 7  is independently selected from the group consisting of hydrogen, OR A , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, dihaloC 1-6 alkyl and trihaloC 1-6 alkyl; 
         each R A  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, phenyl, benzyl and 5-10 membered heterocyclyl, each optionally substituted by from 1 to 3 halogen atoms; and 
         each R B  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, phenyl, benzyl and 5-10 membered heterocyclyl, each optionally substituted by from 1 to 3 halogen atoms. 
       
     
     
       2. A compound as claimed in  claim 1  wherein G is a group selected from: 
       
         
           
           
               
               
           
         
       
     
     
       3. A compound as claimed in  claim 1 , in which R 1  represents N(R B ) 2 , phenyl or a 5-10 membered heterocyclyl, wherein said heterocyclyl is either unsubstituted or said phenyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, and C 1-6 alkyl; and R B  represents C 1-6 alkyl. 
     
     
       4. A compound as claimed in  claim 1 , in which R 1  is selected from C 2-6 alkenyl, N(R B ) 2 , phenyl or 5-10 membered heterocyclyl, wherein said phenyl or heterocyclyl is either unsubstituted or said phenyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, nitro, C 1-6 alkyl, and trihaloC 1-6 alkyl, and each R B  representing C 1-6 alkyl. 
     
     
       5. A compound as claimed in  claim 1 , in which R 3  represents hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, phenyl, or 5-10 membered heterocyclyl wherein said heterocyclyl is either unsubstituted or said phenyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, C 1-6 alkyl and trihaloC 1-6 alkyl. 
     
     
       6. A compound as claimed in  claim 1 , in which R 3  is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl and C 3-8 cycloalkyl. 
     
     
       7. A compound as claimed in  claim 1 , in which each of R 4 , R 5 , R 6  and R 7  is independently selected from the group consisting of hydrogen, halogen and methyl. 
     
     
       8. A compound as claimed in  claim 1 , in which G represents 
       
         
           
           
               
               
           
         
         R 1  represents a 5-membered heterocycle substituted with 2 C 1-3 alkyl; R 2  represents —C(NH 2 )═N—OH; R 3  represents C 1-3 alkyl; R 4  represents fluoro; and R 5 , R 6  and R 7  represent hydrogen. 
       
     
     
       9. A compound as claimed in  claim 1 , in which R 1  is selected from C 2-6 alkenyl, N(R B ) 2 , phenyl or 5-10 membered heterocyclyl, wherein said phenyl or heterocyclyl is either unsubstituted or said phenyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, nitro, C 1-6 alkyl and trihaloC 1-6 alkyl; and each R B  represents C 1-6 alkyl;
 R 2  is selected from the group consisting of —CH═N—OH, and —C(NH 2 )═N—OH; 
 R 3  is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-8 cycloalkyl; and 
 each of R 4 , R 5 , R 6  and R 7  independently represents hydrogen, halogen, cyano, nitro or C 1-6 alkyl. 
 
     
     
       10. A compound as claimed in  claim 9 , in which each of R 4 , R 5 , R 6  and R 7  is independently selected from the group consisting of hydrogen, halogen and methyl. 
     
     
       11. A compound as claimed in  claim 9 , in which R 4  represents hydrogen, halogen or methyl, and R 5 , R 6  and R 7  represent hydrogen. 
     
     
       12. A compound as claimed in  claim 11 , in which R 4  represents fluoro. 
     
     
       13. A compound as claimed in  claim 9 , in which G represents 
       
         
           
           
               
               
           
         
       
     
     
       14. A compound as claimed in  claim 13 , in which G represents 
       
         
           
           
               
               
           
         
       
     
     
       15. A compound as claimed in  claim 9 , in which R 2  is selected from the group consisting of —CH═N—OH, and —C(NH 2 )═N—OH. 
     
     
       16. A compound as claimed in  claim 9 , in which R 3  is C 1-3 alkyl. 
     
     
       17. A compound as claimed in  claim 9 , in which R 1  is selected from phenyl or 5- or 6-membered heterocyclyl, wherein said phenyl or heterocyclyl is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen and C 1-3 alkyl. 
     
     
       18. A compound as claimed in  claim 17 , in which R 1  represents a 5- or 6-membered heterocyclyl, said heterocyclyl being substituted with two C 1-3 alkyl groups. 
     
     
       19. A compound as claimed in  claim 18 , in which R 1  represents a 5-membered heterocyclyl, said heterocyclyl being substituted with two methyl groups. 
     
     
       20. A compound as claimed in  claim 19 , in which said 5-membered heterocyclyl is selected from isoxazolyl, isothiazolyl, pyrrolyl, furanyl, pyrazolyl or thiophenyl. 
     
     
       21. A compound as claimed in  claim 20 , in which said 5-membered heterocyclyl is dimethylisoxazolyl. 
     
     
       22. A compound according to  claim 9 , in which G represents 
       
         
           
           
               
               
           
         
         R 1  is selected from C 2-6 alkenyl, N(R B ) 2 , phenyl or 5-6 membered heterocyclyl, wherein said phenyl or heterocyclyl group is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano and C 1-3 alkyl; and each R B  representing C 1-3 alkyl; 
         R 2  is selected from the group consisting of —CH═N—OH, and —C(NH 2 )═N—OH; 
         R 3  is selected from the group consisting of hydrogen and C 1-6 alkyl; and 
         each of R 4 , R 5 , R 6  and R 7  independently represents hydrogen, halogen or methyl. 
       
     
     
       23. A compound according to  claim 9 , in which G represents 
       
         
           
           
               
               
           
         
         R 1  represents a 5-membered heterocyclyl, said heterocyclyl being substituted with two methyl groups; 
         R 2  is selected from the group consisting of —CH═N—OH, and —C(NH 2 )═N—OH; 
         R 3  is hydrogen or C 1-3 alkyl; 
         R 4  represents halogen; and 
         R 5 , R 6  and R 7  each represent hydrogen. 
       
     
     
       24. A compound as claimed in  claim 1 , which is any one of the following compounds:
 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde oxime; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime; 
 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carboximidamide; 
 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(diethylamino)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide; 
 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(5-bromo-1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carboximidamide; 
 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(2,6-difluorophenyl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-4-carbaldehyde oxime; 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbaldehyde oxime; 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide; 
 1-(3,5-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-N′-hydroxy-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1-(3-fluoro-4-hydroxyphenyl)-N′-hydroxy-1H-pyrazole-4-carboximidamide; 
 1-(2,3-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-N′-hydroxy-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1H-pyrazole-4-carboximidamide; 
 1-(2,3-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1H-pyrazole-4-carbaldehyde oxime (isomer A); 
 1-(2,3-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1H-pyrazole-4-carbaldehyde oxime (isomer B); 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1-(2-fluoro-4-hydroxyphenyl)-1H-pyrazole-4-carbaldehyde oxime; 
 1-(3,5-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1H-pyrazole-4-carbaldehyde oxime; 
 1-(2,5-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-N′-hydroxy-1H-pyrazole-4-carboximidamide; 
 1-(2,5-difluoro-4-hydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-1H-pyrazole-4-carbaldehyde oxime; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-propyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde oxime; 
 1-(2,3-difluoro-4-hydroxyphenyl)-3-ethyl-5-(1-methyl-1H-pyrrol-2-yl)-1H-pyrazole-4-carbaldehyde oxime; 
 2-(2-fluoro-4-hydroxyphenyl)-2′,4′,5-trimethyl-2H,2′H-3,3′-bipyrazole-4-carbaldehyde oxime; 
 2-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-2′,4′,5-trimethyl-2H,2′H-3,3′-bipyrazole-4-carboximidamide; 
 5-(2,6-dimethylphenyl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide; 
 5-(2,6-dimethylphenyl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde oxime; 
 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 1-(2,3-difluoro-4-hydroxyphenyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 1-(3,5-difluoro-4-hydroxyphenyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 4-(2,6-difluorophenyl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(2,6-dichlorophenyl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(2,6-dichlorophenyl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(3,5-dimethylisoxazol-4-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisoxazol-4-yl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide; 
 5-((Z)-but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylpyridin-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxy-2-methylphenyl)-3-methyl-1H-pyrazole-4-carboximidamide; 
 5-(3,5-dimethylisoxazol-4-yl)-3-ethyl-N′-hydroxy-1-(4-hydroxy-2-methylphenyl)-1H-pyrazole-4-carboximidamide; 
 5-(2,5-dimethyl-1H-pyrrol-1-yl)-N′-hydroxy-1-(4-hydroxy-2-methylphenyl)-3-methyl-1H-pyrazole-4-carboximidamide; 
 N′-hydroxy-1-(4-hydroxy-2-methylphenyl)-3-methyl-5-(2-methyl-5-propyl-1H-pyrrol-1-yl)-1H-pyrazole-4-carboximidamide; 
 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(3,5-dimethylisoxazol-4-yl)-3-(3-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisoxazol-4-yl)-3-(3-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide; 
 (Z)-4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxy-2-methylphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 (E)-4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxy-2-methylphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxy-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(2,4-dimethylthiophen-3-yl)-N′-hydroxy-3-(4-hydroxy-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(3,5-dimethylisothiazol-4-yl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(2,6-dimethylphenyl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide; 
 4-(2,4-dimethylfuran-3-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime; 
 4-(3,5-dimethylisothiazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide; 
 or a pharmaceutically acceptable ester, amide, solvate or salt thereof, or a salt of such an ester or amide, or a solvate of such an ester, amide or salt. 
 
     
     
       25. A pharmaceutical composition which comprises a compound as claimed in  claim 1 , together with a pharmaceutically acceptable carrier, and optionally together with a therapeutic agent.